Friday, October 14, 2011

High crimes, deceit, and piracy in international health research

By Prathap Tharyan
Posted on October 14, 2011

The menace of piracy on the high seas, involving modern-day Somali-based seafaring pirates, continues to plague the nautical world. 

What is puzzling is that an apparently motley crew of ill-equipped brigands could hold the combined naval and coast guard fleets of regional and global super-powers at bay, and their governments and people to ransom.

Even more spine-chilling are the tales, increasingly heard, of high crimes, deceit and piracy involving international drug cartels that use sophisticated, and often subtle, methods to deceive and avoid deception; as well as individual fraudsters whose methods, in retrospect, were sometimes clumsy. 

Equally puzzling is the ineptitude of the world in deterring, detecting or dealing with research fraud, even though it affects the lives of many more people than piracy on the high seas does.

Exposing research fraud

In July 2005, a series of articles in the BMJ chronicled the perseverance of its previous editor, Richard Smith, who over a period of more than 10 years had attempted to investigate and publicly expose as fraudulent, the 1992 publication by Dr. Ram B. Singh, a private practitioner from Moradabad, India, and six co-authors. Singh had claimed that patients randomized to take a low-fat, fiber-rich diet had nearly half the risk of dying from any cause over a year’s follow-up, compared to those on a reduced fat diet alone.1  

The journal’s actions included an editorial,2 a detailed account of its failed attempt to find a legitimate authority in India to investigate its concerns and adjudicate,3 a forensic-statistical investigation that concluded that the data from this paper were strongly indicative of fabrication,4 and an “expression of concern” about the validity of the paper.5 

By then, this fraudulent article had already been cited 225 times in other research publications.3

In January 2006, the dean of research affairs at Seoul National University announced that the research reports published in 2004 and 2005 in the prestigious journal Science by Woo Suk Hwang and his co-workers were fabricated. 

These reports, purporting to the production of the first stem cell line produced from a cloned human embryo, and the creation of 11 stem cell lines that genetically matched people with spinal cord injury, diabetes, and an immune system disorder, had been hailed at publication as seminal scientific breakthroughs in stem cell research.6 

What was heralded as the dawn of a new age of novel treatments for a host of hitherto untreatable conditions, dramatically culminated in the international  disgrace of one of South Korea’s national heroes.


Scientists behaving abysmally

These, and many other, high-profile and scandalous instances of fraudulent research have blighted the image of health science researchers as objective and respected scientists in search of the truth. 

While many scientists are above reproach and their work is laudable, scientific fraud appears to be on the rise. This is evidenced by a sharp increase in papers retracted in PubMed over the past decade due to research misconduct.7 

Research misconduct (fabrication, falsification and plagiarism) is not restricted to the usual suspects, such as researchers from India or China, but involves virtually every country where research is undertaken. In one survey, papers identified as retracted in PubMed due to research misconduct, rather than errors, involved more US authors than from other countries.8 This startling revelation could merely reflect the North American preponderance of journals indexed in PubMed, and, perhaps, greater alertness by their peer-reviews, editors, and readers in suspecting and confirming research fraud. 


Repeat offenders or isolated offenses?

The BMJ editorial and related articles also raised suspicions about many of Singh’s previous publications. 

In the same month and year as the BMJ exposed Dr. Ram B. Singh, the Lancet published an “expression of concern” by its editor, Richard Horton, with details of the investigations and findings that indicted Dr. Singh of fabricating a previous Lancet paper.9

Earlier in February 2005, the editor of Nutrition retracted as fraudulent, a 2001 paper by a Canadian researcher who now lives and works in India, Ranjit Kumar Chandra.10 

In this publication, Chandra claimed that elderly people randomized to physiological amounts of vitamins and trace elements had improved cognitive functions compared to those given a placebo. This paper had been earlier rejected by the BMJ due to concerns about data fabrication during peer review.  

Serious doubts were also expressed in 2003 about another similar study by Chandra published in in 1992 in the Lancet that had been cited more than 300 times.10 In 2006, the Canadian Broadcasting Corporation aired serious doubts about several of Dr. Chandra’s other previous publications.10

From 2000 to 2010, PubMed identified 788 research studies in the English language as having being retracted by journals, mostly due to errors or for ambiguous reasons. However, 27% of these retractions were for data fabrication, falsification, or data plagiarism, and less commonly due to plagiarism of the ideas or the words of others. 

As in the cases of Singh and Chandra, approximately 53% of these fraudulent retracted papers were by repeat offenders with prior retracted publications.8 

Investigating previous publications by fraudulent authors is necessary, but proving fraud is often difficult. When an detailed investigation does occur, as it did with John Darsee, a one-time protégé of the eminent Harvard cardiologist Eugene Braunwald, over 100 of his previous studies were also found be fabricated.10


The impact of fraudulent research

Fraudulent research is often published in prestigious journals with high Impact Factors. Fraud is difficult to prove as fabricated or falsified papers are often indistinguishable from non-fraudulent ones. 

Even if suspicions of fabrication are substantiated, over a third of fraudulent papers are either never retracted, or are slow in being retracted; particularly when senior researchers are implicated. 

Such retractions are also not readily evident, as the statement of concern or retraction appears in subsequent issues of the journal, and the fraudulent article continues to be available unaltered. The PubMed abstract for the fraudulent paper carries a citation and link to the journal’s statement of retraction, or concern; but this is usually identified as a comment rather than a retraction. Even if these links are checked, access to the content of the comment may be limited by access to the journals, if they are not open access publications.

Fraudulent papers, even if retracted, continue to be cited and influence subsequent research.  

One conservative estimate identified over 5000 citations in 851 secondary studies to 180 primary studies involving clinical research in humans that were identified as retracted due to fraud in PubMed. The 180 retracted fraudulent primary studies enrolled 28,000 people, 9189 of whom were in the treatment arms; the 851 secondary studies which cited a retracted paper enrolled 400,000 people, of whom 70,501 patients were allocated to the dubious experimental interventions.11 

In another example, a retracted paper continued to be cited in high impact journals even as long as 24 years after retraction.12

Given the likelihood that many fraudsters were repeat offenders, it is worrying that these numbers reflect only a fraction of the actual number of fraudulent primary research publications. 

Also inestimable is the number of secondary publications that cite them or test the effects of supposedly effective and safe treatments on unsuspecting research subjects.  

Even if not evaluated in further research, using the results of fraudulent research may result in harm, or deny people the benefits of alternative and better proven interventions. 


Dealing with research misconduct

Investigating and dealing firmly with research misconduct is important, but the question of who should investigate is far from clear. 

Richard Smith and the BMJ served as whistle-blowers in the Singh case but, as Smith argues, while journals do have a duty to inform its readers, they do not have sufficient legitimacy to investigate or to initiate due process.10 

Journals are well advised to have an ethics committee to provide independent guidance regarding the complex ethical issues journals and editors’ face. This  helped the BMJ decide on making public the dismal saga involving Singh.13
The organization ideally placed to initiate investigations when fraudulent research is suspected or reported is the employing institution, often a medical college, university, or hospital.2 

Unfortunately, it is highly doubtful whether most such institutions in India, or in other resource constrained countries, have established processes or mechanisms, or the will, to deal with issues pertaining to breaches of research integrity. The situation becomes more complex when the accused is also part of the management, or the head as in the case of Singh, of a private institution. 

Regulatory bodies such as the Office of the Drug Controller General of India, and the Medical Council of India, as well government agencies such as the Indian Council of Medical Research (ICMR), and its parent organization, the Department of Health Research, could promulgate measures to investigate and deal with allegations of research misconduct. 

However, unless the many draft bills currently languishing in parliament that pertain to these agencies include effective statutory provisions to deal with such allegations, it is inconceivable that these bodies will be empowered effectively to deal with allegations of research misconduct. 

The Medical Council of India, in its current and future avatars, needs to consider dealing with researchers accused of misconduct as a legitimate activity within its purview; but even if that unlikely event does miraculously happen, mechanisms to deal with fraudulent research by non-medical researchers are also needed.

Research misconduct and violation of human rights

The National Human Rights Commission (NHRC) has the powers of a civil court and can summon records in the public domain. It can initiate investigations into allegations of violations of human rights or their abetment, or negligence by a public servant in preventing such violations. 

In the investigations into the allegations against Singh, the NHRC forwarded the complaint from the BMJ to the Indian Council of Medical Research that in turn pleaded inability to take disciplinary action against a person not employed by the ICMR.3 

If the study in question was funded by the ICMR, or another funding agency, then the funding agency could initiate the request for an investigation, but would require the full cooperation of the accused researcher and implicated co-researchers, as well as the host institution(s). 

Hopefully, the NHRC will see it fit to initiate investigations, should allegations of misconduct be received in the future, since it appears that no other organization in India is willing, or equipped, to deal with allegations of this nature.  

Undertaking research on human subjects and falsifying results, or publishing fraudulent research in the public domain that can harm others, is surely a violation of the human rights of numerous people. 

However, Chapter VII, 36 (2) of the Protection of Human Rights Act, 1993 [As amended by the Protection of Human Rights (Amendment) Act, 2006–No. 43 of 2006] limits the period of enquiry that the NHRC or a state commission is empowered to deal with, to within a year of commitment of the violation. 

Greater clarity is needed in determining what exactly this means in the context of investigating allegations of research misconduct.  

The NHRC is also mandated in Chapter III, 12 (g) of the above Act to “undertake and promote research in the field of human rights.” 

The link to “Research Studies and Projects” in the website of the NHRC details the many completed research studies and those in progress. However, none deal with any aspect of research misconduct.


Can you help?

Are you concerned about the issues raised in this blog-post?

Are there legal experts out there who are willing to provide advice on what legal mechanisms one can employ to deal with allegations of research misconduct, should institutional mechanisms fail? 

Are there young researchers interested in approaching the NHRC or the ICMR to seek sponsorship to undertake qualitative and quantitative research regarding research misconduct in India? 

Are you aware of any initiatives to prevent research misconduct and if such initiatives have had any measured outcomes or impact? 

Is anyone interested in registering a title and undertaking a systematic review (perhaps jointly undertaken by the Cochrane Collaboration and the Campbell Collaboration) on “Interventions to prevent research misconduct”? Neither The Cochrane Library nor The Campbell Library currently contains such a systematic review. 

If the answer to any of the above questions is affirmative, do post a comment.

Also do watch this space for more blog-posts on: Deception in international health research, and on a hitherto unknown international detective agency that is working tirelessly to expose high crimes, deceit, and piracy in international health research.

About the author: 
Prathap Tharyan is Professor of Psychiatry at the Christian Medical College, Vellore, Tamil Nadu, India. He is also Director of the South Asian Cochrane Network & Centre, an independent Centre of the Cochrane Collaboration. Evidence-Informed Musings is an activity of the Effective Health Care Research Consortium

The views expressed in this blog-post are those of the author and are not necessarily shared by any of the organizations named herein, their partners, or any funding agency. 

E-mail the author at:


Monday, October 3, 2011

Evidence-Based Medicine, inflight-emergencies, and the responsibility of airlines

By Prathap Tharyan
Posted on October 3, 2011

Akshay Sharma, in a courageous first person account in the National Medical Journal of India, details his experience of dealing with a medical emergency in a four year old child who was unresponsive and dehydrated due to  repeated vomiting after a pre-boarding airport snack, while on a trans-Atlantic flight 30,000 feet above sea level.1
As an itinerant traveler, and having been caught in similar predicaments, I commend Akshay for his courage in responding to the medical emergency and upholding the integrity and ideals of the medical profession so far removed  from the safe confines of a well-equipped hospital. 
I also admire his candor in admitting his initial reluctance to get involved in a potentially critical situation, fraught as it was with potential medico-legal implications and the possibility of public embarrassment. 
In the real world, heroic acts are often spawned from fear or compulsion, but completion of the act in the manner that Akshay did, in taking a carefully considered decision that led to the safe recovery of the ill child, speaks of quiet confidence in his own abilities and awareness of his limitations, given the constraints imposed by his situation, and his level of experience as an intern in training. 

Was Akshay’s response “evidence-based”?
Akshay suggests that his action, of securing intravenous access and providing intravenous fluids to the child contrary to the advice provided by the Medilink ground team contacted by the aircrew by tele-link to initially try a conservative approach, was not “evidence-based”. 
I submit that this is not necessarily true and is based on a common mis-perception that evidence-based medicine only concerns the incorporation of external evidence (ideally from systematic reviews of interventional trials) as the sole basis for medical interventions. 
The true linchpin of Evidence-Based Medicine, or more appropriately “Evidence-Informed Healthcare” is the astute clinician who has the skills to rapidly and accurately diagnose the clinical condition and consider prognostic issues; the expertise to access and interpret the reliability of the best available evidence; and to assess the applicability of the evidence within the context and constraints of healthcare provision. The wishes of the patient and his or her family would also be important, 2though less pressingly so in a medical emergency.3
In his report Askhay demonstrated all the essential attributes of evidence-informed health decision making byassessing various interventional options based on the uncertain probability (unstated in the report) of oral promethazine acting rapidly enough to prevent further vomiting, worsening dehydration, and leading to a situation where securing intravenous access in the four-year old could pose difficulties. 
In clinical situations, particularly in emergencies, one tends to use Bayesian logic based on one’s assessment of multiple parameters, their probabilities of occurrence, and the likelihood of success with different interventions to decide on options, rather than the more linear approach often followed in classical evidence-based medical teaching. 

In-flight emergencies and the availability of adequate medical cover
What might have reassured Akshay in this crisis was the opportunity to discuss his reasoning and to have this approved by the Medlink ground team. This facility is not always available on all airlines. 
In the three instances I was reluctantly thrust in to responding to in-flight emergencies, fellow “medical” passengers turned out to be laboratory personnel, or those who pleaded inexperience, leaving me, a psychiatrist, to deal with the emergencies! Fortunately the emergencies were self-limiting.

The good, the not so good, and the plain ugly facts about in-flight emergencies

The first involved food poisoning in an adult that settled with conservative management; the second an epileptic seizure in an adult on a transatlantic flight caused by sleep deprivation and irregular anti-epileptic medication that required only masterly inactivity and advancement of the scheduled antiepileptic dose. In the third,an unresponsive elderly gentleman came around from a syncope after a few minutes of ensuring airway patency with an Ambu-bag. 
In all three situations, the aircrew did not have access to more experienced help. They also seemed uncomfortable with my abilities to deal with the situation when my interventions were not immediately successful, since I had declared I was a psychiatrist. 
In all three instances, my internal turmoil was inversely proportional to my external calm and sense of control I endeavored to convey, while silently issuing volleys of prayers for divine intervention and hoping the height we were at would ensure better communication with the Almighty. 
In all three situations, I too, like Akshay, was a reluctant ‘volunteer”, whose decision to volunteer was taken for me by nosy, but well-meaning, co-passengers who had “discovered” my profession and sought free medical advice for their ailments,at the expense of my forfeiting the privilege of settling down to watch in-flight movies with some liquid refreshments! 
Also in all three instances, the aircrew rewarded my contributions by bumping me up to business class, or providing me with voucher upgrades, or by a long chat with a charming air-hostess!
A more disastrous outcome occurred in Mumbai airport in 2002, when on arrival from a tiring overseas trip, and while awaiting a domestic transit flight, a middle aged gentleman dropped unconscious with a cardiac arrest in the transit terminal at around three am. A fellow passenger and I attempted cardiopulmonary resuscitation unsuccessfully and gave up after 25-30 minutes. There were no medical facilities or medical emergency equipment that we could access on site, and emergency medical personnel summoned arrived too late to do any good. 

The responsibility of airlines
The next time you take a long-haul flight, it might be prudent to enquire to the readiness of your chosen airline to deal with in-flight medical emergencies. 
In today’s world of increasing global travel, airlines and airports that rely on the fortuitous presence in their passenger lists of trained medical personnel willing to help in emergencies, and with the competence to do so, is simply not good enough. 
Airlines need to ensure that their aircrews are adequately trained to deal with medical emergencies, the relevant emergency equipment and supplies are on board, evidence-based emergency manuals are available for reference, and tele-links to emergency medical help are routinely available. 
Passengers should be provided with precautions to be followed to prevent medical mishaps on long-haul flights, and the facilities available to deal with them, should they occur. 
Medically trained passengers who are willing to help in medical emergencies could be identified a-priori, or at the time of booking tickets, and provided with additional training and information about emergency equipment available on board. They could be provided frequent flyer benefits for enrollment and for services rendered, as these are not considered as compensation.5
All airports should have emergency help available round the clock, response times checked, contact numbers prominently displayed and clinical audits undertaken on adequacy of responses, response times, and outcomes. 
Finally, the institution of these measures, and additional ones, on the reduction in undesirable outcomes after in-flight and in-transit medical emergencies should be properly evaluated, and a common registry created. 
This issue is clearly topical and some other suggestions that airlines ought to follow to deal with in-flight emergencies are provide in a recent JAMA article.4
Emergency measure for those responding to in-flight emergencies to institute in particular emergencies are detailed in a Lancet report.5

What is the evidence regarding managing in-flight emergencies?
I could not find a Cochrane Systematic review in The Cochrane Library on “Interventions to prevent adverse outcomes during in-flight or in-transit medical emergencies”. 
There is a Cochrane systematic review on the use of “Compression stockings for preventing deep-vein thrombosis in airline passengers”, 6and another on, “Melatonin for the prevention and treatment of jet lag”.Both interventions are recommended by the reviews.
There are possibly other systematic reviews dealing with individual medical emergencies on long-haul flights in The Cochrane Library, and it would help if the publishers could also provide a collection of reviews pertaining to travel medicine in addition to the current collections they display on their home page.

Not a one-off event
As an aside, Akshay Sharma is one of the founding members of Informer, an initiative of medical students that seek to improve the ability of medical students to understand, and to contribute to, research. Akshay is also one of the guiding lights behind the Cochrane Student’s Journal Club
If more of “tomorrow’s doctors” display the kind of initiative and enthusiasm towards the medical profession and the use of reliable evidence that Akshay and his young colleagues do, then the rest of us can rest easy that the ideals of our profession will be nurtured and health outcomes improved; and also enjoy more fully the benefits of international air travel.